The biological bases of depression


The biological bases of depression

As a medical student in the 1970s, Torbjörn Bäckström was perplexed as to why a woman who appeared to be in good mental health was being kept in a psychiatric facility.

The woman would be admitted once a month due to her violent behaviour and attacks on others, Bäckström and his coworkers later discovered. Bäckström, an endocrinologist and emeritus professor at Ume University in Sweden, recalls, "This was becoming a sort of pattern, that when we came there after she had been taken in by force, she did not understand what had happened and why it had happened.

Bäckström focused on two specifics. One was the apparent correlation between her violent outbursts and menstruation. The second was a section on premenstrual syndrome and the impact of hormones on the brain found in a physiology textbook.

His research career was begun by these two findings, and he concentrated on steroid hormones and their neurological consequences. From a brief mention in a textbook to the 2019 approval of the first medication in a new class of antidepressants, he has witnessed the field's development during this time. Brexanolone, sold under the brand name Zulresso, is a neuroactive steroid, a hormone that affects brain chemistry. It is the only medication designed particularly to treat post-partum depression.

Neuroactive steroid hormone interactions with the brain are intricate, cyclical, and very unique. It's not just a matter of the hormones being too high or too low; rather, it's a result of how the brain reacts to variations in the hormones' levels. Premenstrual dysphoric disorder (PMDD), which is the onset of a combination of physical and psychological symptoms linked to menstruation, and other mood disorders with hormonal triggers are further complicated by definitions that are either too tight, not stringent enough, or non-existent. Clinical trials are complicated by this ambiguity.

In an effort to develop more accurate diagnoses and forms of treatment, research teams from all around the world are looking into how changes in hormone levels might cause or exacerbate mental health issues like depression.

Focusing on GABA

Allopregnanolone, a neuroactive steroid created by the breakdown of the hormone progesterone, is the first commercial product of this neuroscientific awakening.

Allopregnanolone levels gradually increase throughout pregnancy, reaching their peak in the third trimester. After the baby is born, they significantly decline. Post-natal depression is thought to be significantly influenced by this quick drop. In many people, the levels return to normal within a few days, but in some, they don't; in these people, severe depression and withdrawal might set in.

Brexanolone is an allopregnanolone formulation that was made available in 2019 by the Cambridge, Massachusetts-based biopharmaceutical company Sage Therapeutics. It is administered intravenously to sufferers of severe postpartum depression. For some, the clinical benefits were profound.

The brain's -aminobutyric acid type A receptor is what allopregnanolone binds to (GABAA). Since GABA is an inhibitory neurotransmitter, it inhibits rather than stimulates neuronal activity. The brain's GABA system is thought to play a role in a number of mental health issues, including depression.

In the same way that benzodiazepines, a family of sedatives that have been around since the 1950s and includes medications like Valium, target the GABAA receptor, another substance called zuranolone that Sage Therapeutics is developing as an oral treatment for major depressive disorder does as well. Brexanolone and zuranolone, however, also interact with GABAA receptors on areas of the cell known as extrasynaptic receptors, in contrast to benzodiazepines, which only do so in the synaptic connections between neurons. According to Jeff Jonas, chief innovation officer at Sage Therapeutics, the interaction with synaptic receptors "controls the moment-to-moment inhibitory tone in the brain, sort of like the weather." Contrarily, "the total inhibitory tone is controlled by the interaction with other GABAA receptors, which is more like the climate."

Instead of short-term inhibition of neuronal activity, sustained change over time is the aim. In a 2021 study, participants with postpartum depression received a two-week course of zuranolone, and their depression scores decreased. This effect persisted for 45 days after treatment began.

The neuroactive steroids' quick onset of action is another peculiar quality, according to Bernard Ravina, chief medical officer at Praxis Precision Medicines in Boston, Massachusetts. These substances have been developed by Praxis to combat the serious depressive disorder. Additionally, substances that operate on the GABAA receptor appear to start working within a few days, in contrast to conventional antidepressants, which might take weeks or months to fully take action. That's a significant component of the attractiveness, says Ravina.

Allopregnanolone, however, is only the beginning of the neurosteroid saga. Director of the Johns Hopkins Center for Women's Reproductive Mental Health in Baltimore, Maryland, Lauren Osborne, says "We also have to think about the interaction between the hormones and what they are attaching to." Osborne points out that the changing levels of allopregnanolone and other hormones during pregnancy might also change the structure and function of the GABAA receptor.

Furthermore, according to Tory Eisenlohr-Moul, a clinical psychologist at the University of Illinois in Chicago, many times those who suffer from severe mood disorders don't have aberrant hormone levels. She surmises that the GABAA receptor is the issue.

The GABAA receptor's subunits may respond differently to fluctuations in hormone and neurosteroid levels during the menstrual cycle in persons with PMDD, according to a study by Eisenlohr-team. Moul's According to the researchers' theory, the receptor is not properly adapting or reacting to the hormonal fluctuations, which causes either an under- or an over-reaction to the changes in hormone levels.

Identification and treatment

Some people suffer greater symptoms of hormone shifts than others do between the beginning of menstruation and the conclusion of menopause. Estimates of post-natal depression4 range from 4% to almost 64%, and approximately 5% of women of reproductive age develop PMDD3. Around menopause, up to 40% of women report having depressive symptoms.

Despite the fact that these hormonal mood disorders are common, diagnosing them can be challenging because of the wide range of symptoms and timings that are present in the clinical presentation. The clinical diagnosis of PMDD, however, according to psychiatrist Jayashri Kulkarni, head of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, is very specific in the most recent Diagnostic and Statistical Manual of Mental Disorders, for instance.

According to the 28-day cycle, "it must be a very clear, seven-day deterioration in mood exactly one week before menstruating," she explains. “Well, that only exists in textbooks.”

According to Eisenlohr-research Moul's with her own patients, there are variations in the timing of PMDD symptoms with respect to the menstrual cycle. Some people experience symptoms like irritation just after ovulation, while others feel depressed and exhausted right before their period starts (typically 14 days before ovulation).

Similar to this, scientists have not yet discovered any reliable and objective biological indicators of alterations in brain chemistry that may be utilised to identify perimenopausal depression. Even blood hormone levels do not accurately reflect what is happening in the brain. The physical symptoms of menopause might appear up to five years after the psychological ones, which makes diagnosing perimenopausal depression more challenging.

Additionally, it is unclear how much of the depression and anxiety that first-time menstruators, pregnant women, and menopausal women suffer is due to non-biological causes. These stages of life sometimes coincide with stressful events like having children, raising a family, and, in later years, possibly looking after elderly parents or dealing with retirement.

However, Ravina contends that there is strong evidence for a biological basis for mood disorders. The fact that hormones affect mood problems in everyone strengthens this argument. The evidence suggests that depressed individuals, regardless of gender, have decreased endogenous levels of these neuroactive hormones and modifications to extrasynaptic receptors, according to Ravina. "Depression in such hormone fluctuation reproductive situations has a definite biological basis"

The worry that tying hormones to mood may feed the false idea that women are enslaved by hormones may be lessened by the reality that hormones and their neuroactive metabolites are linked to mood problems in both men and women. Eisenlohr-Moul agrees that the destigmatization of these hormonally related conditions has been aided by research into the relationship between hormones and the brain; for instance, rude jokes regarding premenstrual syndrome are far less prevalent today than they were even 20 years ago.

According to Eisenlohr-Moul, "it's an abnormal brain response to normal hormone fluctuations and it may be treated." This isn't a joke. It's crippling and it affects someone's life.

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